Sustained release formulations of oxymorphone

ABSTRACT

Sustained release formulations of oxymorphone or pharmaceutically acceptable salts thereof; methods for making the sustained release formulations of oxymorphone or pharmaceutically acceptable salts thereof; and methods for using the sustained release formulations of oxymorphone or pharmaceutically acceptable salts thereof to treat patients suffering from pain are provided.

RELATED APPLICATIONS

This application is a continuation of and claims priority under 35U.S.C. § 120 to U.S. patent application Ser. No. 10/189,932, filed onJul. 3, 2002, entitled “Sustained Release Formulations of Oxymorphone,”which claims priority under 35 U.S.C. § 119(e) to U.S. ProvisionalApplication No. 60/329,426 filed Oct. 15, 2001, U.S. ProvisionalApplication No. 60/329,352 filed Oct. 15, 2001, and to U.S. ProvisionalApplication No. 60/303,357 filed Jul. 6, 2001, the disclosures of whichare incorporated by reference herein in their entirety.

FIELD OF THE INVENTION

The invention provides sustained release formulations of oxymorphone andpharmaceutically acceptable salts thereof; methods for making thesustained release formulations of oxymorphone and pharmaceuticallyacceptable salts thereof; and methods for using the sustained releaseformulations of oxymorphone and pharmaceutically acceptable saltsthereof to treat patients suffering from pain.

BACKGROUND OF THE INVENTION

Pain is the most frequently reported symptom and it is a common clinicalproblem which confronts the clinician. Many millions of people in theUnited States suffer from severe pain that is chronically undertreatedor inappropriately managed. The clinical usefulness of the analgesicproperties of opioids has been recognized for centuries, and morphineand its derivatives have been widely used for analgesia for decades in avariety of clinical pain states.

Oxymorphone HCl (14-hydroxydihydromorphinone hydrochloride) is asemi-synthetic phenanthrene-derivative opioid agonist, used in thetreatment of acute and chronic pain, with analgesic efficacy comparableto other opioid analgesics. Oxymorphone is currently marketed as aninjection (1 mg/ml in 1 ml ampules; 1.5 mg/ml in 1 ml ampules; 1.5 mg/mlin 10 ml multiple dose vials) for intramuscular, subcutaneous, andintravenous administration, and as 5 mg rectal suppositories. At onetime, a 10 mg oral immediate release tablet formation of oxymorphone HClwas marketed. Oxymorphone HCl is metabolized principally in the liverand undergoes conjugation with glucuronic acid and reduction to 6 alphaand beta hydroxy epimers.

An important goal of analgesic therapy is to achieve continuous reliefof chronic pain. Regular administration of an analgesic is generallyrequired to ensure that the next dose is given before the effects of theprevious dose have worn off. Compliance with opioids increases as therequired dosing frequency decreases. Non-compliance results insuboptimal pain control and poor quality of life outcomes. Scheduledrather than “as needed” administration of opioids is currentlyrecommended in guidelines for their use in treating chronicnon-malignant pain. Unfortunately, evidence from prior clinical trialsand clinical experience suggests that the short duration of action ofimmediate release oxymorphone would necessitate 4-hourly administrationsin order to maintain optimal levels of analgesia in patients withchronic pain. Moreover, immediate release oxymorphone exhibits low oralbioavailability, because oxymorphone is extensively metabolized in theliver.

There is a need in the art for new formulations of oxymorphone thatrequire less frequent dosing. The invention is directed to these, aswell as other, important ends.

SUMMARY OF THE INVENTION

The invention provides compositions comprising oxymorphone or apharmaceutically acceptable salt thereof and a sustained releasedelivery system, where the sustained release delivery system comprisesat least one hydrophilic compound, at least one cross-linking agent(which may be cationic) and at least one pharmaceutical diluent. Thesustained release delivery system may further comprise one or moreadditional hydrophobic polymers or cross-linking compounds. Thecompositions may optionally comprise an outer coating comprising atleast one water insoluble compound, and optionally one or moreplasticizers and/or water soluble compounds.

The invention provides compositions comprising an inner core and anouter sustained release coating, where the inner core comprisesoxymorphone or a pharmaceutically acceptable salt thereof and the outersustained release coating comprises at least one water insolublecompound. The outer sustained release coating may optionally furthercomprise one or more plasticizers and/or water soluble compounds.

The invention provides methods for treating pain in patients byadministering an effective amount of any of the compositions of theinvention. The pain may be moderate to severe, and may be acute orchronic.

The invention also provides methods for making such compositions.

These and other aspects of the invention are described in detail herein.

BRIEF DESCRIPTION OF THE FIGURE

FIG. 1 is a linear scale graph, without standard deviations, showing themean oxymorphone plasma concentration versus time for patients treatedwith the sustained release oxymorphone tablets of the invention afterfasting (A), for patients treated with sustained release oxymorphonetablets of the invention after a high fat meal (B), for patients treatedwith an oxymorphone solution after fasting (C), and for patients treatedwith an oxymorphone solution after a high fat meal (D).

DETAILED DESCRIPTION OF THE INVENTION

To overcome the difficulties associated with the very lowbioavailability of the oral immediate release formulation of oxymorphoneand with a 4 hourly dosing frequency of oxymorphone, the inventionprovides an oral sustained release formulation of oxymorphone comprisingan analgesically effective amount of oxymorphone or a pharmaceuticallyacceptable salt thereof. The bioavailability of the oral sustainedrelease formulations of the invention is sufficiently high that thesustained release formulations can be used to treat patients sufferingfrom pain with only once or twice daily dosing.

The invention provides compositions comprising oxymorphone or apharmaceutically acceptable salt thereof and a sustained releasedelivery system, wherein the sustained release delivery system comprises(i) at least one hydrophilic compound, at least one cross-linking agent,and at least one pharmaceutical diluent; (ii) at least one hydrophiliccompound, at least one cross-linking agent, at least one pharmaceuticaldiluent, and at least one hydrophobic polymer; (iii) at least onehydrophilic compound, at least one cross-linking agent, at least onepharmaceutical diluent, and at least one cationic cross-linking agentdifferent from the first cross-linking agent; (iv) at least onehydrophilic compound, at least one cross-linking agent, at least onepharmaceutical diluent, at least one cationic cross-linking compounddifferent from the first cross-linking agent, and at least onehydrophobic polymer; (v) at least one hydrophilic compound, at least onecationic cross-linking compound, and at least one pharmaceuticaldiluent; or (vi) at least one hydrophilic compound, at least onecationic cross-linking compound, at least one pharmaceutical diluent,and at least one hydrophobic compound.

The oxymorphone may be homogeneously dispersed in the sustained releasedelivery system. Preferably, the oxymorphone or pharmaceuticallyacceptable salt thereof may be present in the composition in an amountof about 1 mg to about 200 mg, more preferably in an amount of about 1mg to about 100 mg, even more preferably in an amount of about 5 mg toabout 80 mg. Preferably, the sustained release delivery system may bepresent in the composition in an amount from about 80 mg to about 420mg, more preferably from about 80 mg to about 360 mg, even morepreferably from about 80 mg to about 200 mg. “Oxymorphone” includesoxymorphone, metabolites thereof, derivatives thereof, and/orpharmaceutically acceptable salts thereof. Metabolites of oxymorphoneinclude, for example, 6-hydroxy-oxymorphone (e.g.,6-α-hydroxy-oxymorphone and/or 6-β-hydroxy-oxymorphone).

Oxymorphone may be in the form of any pharmaceutically acceptable saltknown in the art. Exemplary pharmaceutically acceptable salts includehydrochloric, sulfuric, nitric, phosphoric, hydrobromic, maleric, malic,ascorbic, citric, tartaric, pamoic, lauric, stearic, palmitic, oleic,myristic, lauryl sulfuric, napthalinesulfonic, linoleic, linolenic acid,and the like. The hydrochloride salt of oxymorphone is preferred.

The sustained release delivery system comprises at least one hydrophiliccompound. The hydrophilic compound preferably forms a gel matrix thatreleases the oxymorphone or the pharmaceutically acceptable salt thereofat a sustained rate upon exposure to liquids. The rate of release of theoxymorphone or the pharmaceutically acceptable salt thereof from the gelmatrix depends on the drug's partition coefficient between thecomponents of the gel matrix and the aqueous phase within thegastrointestinal tract. In the compositions of the invention, the weightratio of oxymorphone to hydrophilic compound is generally in the rangeof about 1:0.5 to about 1:25, preferably in the range of about 1:0.5 toabout 1:20. The sustained release delivery system generally comprisesthe hydrophilic compound in an amount of about 20% to about 80% byweight, preferably in an amount of about 20% to about 60% by weight,more preferably in an amount of about 40% to about 60% by weight, stillmore preferably in an amount of about 50% by weight.

The hydrophilic compound may be any known in the art. Exemplaryhydrophilic compounds include gums, cellulose ethers, acrylic resins,polyvinyl pyrrolidone, protein-derived compounds, and mixtures thereof.Exemplary gums include heteropolysaccharide gums and homopolysaccharidegums, such as xanthan, tragacanth, pectins, acacia, karaya, alginates,agar, guar, hydroxypropyl guar, carrageenan, locust bean gums, andgellan gums. Exemplary cellulose ethers include hydroxyalkyl cellulosesand carboxyalkyl celluloses. Preferred cellulose ethers includehydroxyethyl celluloses, hydroxypropyl celluloses,hydroxypropylmethyl-celluloses, carboxy methylcelluloses, and mixturesthereof. Exemplary acrylic resins include polymers and copolymers ofacrylic acid, methacrylic acid, methyl acrylate and methyl methacrylate.In some embodiments, the hydrophilic compound is preferably a gum, morepreferably a heteropolysaccharide gum, most preferably a xanthan gum orderivative thereof. Derivatives of xanthan gum include, for example,deacylated xanthan gum, the carboxymethyl esters of xanthan gum, and thepropylene glycol esters of xanthan gum.

In another embodiment, the sustained release delivery system may furthercomprise at least one cross-linking agent. The cross-linking agent ispreferably a compound that is capable of cross-linking the hydrophiliccompound to form a gel matrix in the presence of liquids. As usedherein, “liquids” includes, for example, gastrointestinal fluids andaqueous solutions, such as those used for in vitro dissolution testing.The sustained release delivery system generally comprises thecross-linking agent in an amount of about 0.5% to about 80% by weight,preferably in an amount of about 2% to about 54% by weight, morepreferably in an amount of about 20% to about 30% by weight more, stillmore preferably in an amount of about 25% by weight.

Exemplary cross-linking agents include homopolysaccharides. Exemplaryhomopolysaccharides include galactomannan gums, such as guar gum,hydroxypropyl guar gum, and locust bean gum. In some embodiments, thecross-linking agent is preferably a locust bean gum or a guar gum. Inother embodiments, the cross-linking agents may be alginic acidderivatives or hydrocolloids.

When the sustained release delivery system comprises at least onehydrophilic compound and at least one cross-linking agent, the ratio ofhydrophilic compound to cross-linking agent may be from about 1:9 toabout 9:1, preferably from about 1:3 to about 3:1.

The sustained release delivery system of the invention may comprise oneor more cationic cross-linking compounds. Cationic cross-linkingcompound may be used instead of or in addition to the cross-linkingagent. The cationic cross-linking compounds may be used in an amountsufficient to cross-link the hydrophilic compound to form a gel matrixin the presence of liquids. The cationic cross-linking compound ispresent in the sustained release delivery system in an amount of about0.5% to about 30% by weight, preferably from about 5% to about 20% byweight.

Exemplary cationic cross-linking compounds include monovalent metalcations, multivalent metal cations, and inorganic salts, includingalkali metal and/or alkaline earth metal sulfates, chlorides, borates,bromides, citrates, acetates, lactates, and mixtures thereof. Forexample, the cationic cross-linking compound may be one or more ofcalcium sulfate, sodium chloride, potassium sulfate, sodium carbonate,lithium chloride, tripotassium phosphate, sodium borate, potassiumbromide, potassium fluoride, sodium bicarbonate, calcium chloride,magnesium chloride, sodium citrate, sodium acetate, calcium lactate,magnesium sulfate, sodium fluoride, or mixtures thereof.

When the sustained release delivery system comprises at least onehydrophilic compound and at least one cationic cross-linking compound,the ratio of hydrophilic compound to cationic cross-linking compound maybe from about 1:9 to about 9:1, preferably from about 1:3 to about 3:1.

Two properties of desirable components of this system (e.g., the atleast one hydrophilic compound and the at least one cross-linking agent;or the at least one hydrophilic compound and at least one cationiccross-linking compound) that form a gel matrix upon exposure to liquidsare fast hydration of the compounds/agents and the ability to form a gelmatrix having a high gel strength. These two properties, which areneeded to achieve a slow release gel matrix, are maximized in theinvention by the particular combination of compounds (e.g., the at leastone hydrophilic compound and the at least one cross-linking agent; orthe at least one hydrophilic compound and the at least one cationiccross-linking compound). For example, hydrophilic compounds (e.g.,xanthan gum) have excellent water-wicking properties which provide fasthydration. The combination of hydrophilic compounds with materials thatare capable of cross-linking the rigid helical ordered structure of thehydrophilic compound (e.g., cross-linking agents and/or cationiccross-linking compounds) thereby act synergistically to provide a higherthan expected viscosity (i.e., high gel strength) of the gel matrix.

The sustained release delivery system further comprises one or morepharmaceutical diluents known in the art. Exemplary pharmaceuticaldiluents include monosaccharides, disaccharides, polyhydric alcohols andmixtures thereof. Preferred pharmaceutical diluents include, forexample, starch, lactose, dextrose, sucrose, microcrystalline cellulose,sorbitol, xylitol, fructose, and mixtures thereof. In other embodiments,the pharmaceutical diluent is water-soluble, such as lactose, dextrose,sucrose, or mixtures thereof. The ratio of pharmaceutical diluent tohydrophilic compound is generally from about 1:8 to about 8:1,preferably from about 1:3 to about 3:1. The sustained release deliverysystem generally comprises one or more pharmaceutical diluents in anamount of about 20% to about 80% by weight, preferably about 35% byweight. In other embodiments, the sustained release delivery systemcomprises one or more pharmaceutical diluents in an amount of about 40%to about 80% by weight.

The sustained release delivery system of the invention may comprise oneor more hydrophobic polymers. The hydrophobic polymers may be used in anamount sufficient to slow the hydration of the hydrophilic compoundwithout disrupting it. For example, the hydrophobic polymer may bepresent in the sustained release delivery system in an amount of about0.5% to about 20% by weight, preferably in an amount of about 2% toabout 10% by weight, more preferably in an amount of about 3% to about7% by weight, still more preferably in an amount of about 5% by weight.

Exemplary hydrophobic polymers include alkyl celluloses (e.g., C₁₋₆alkyl celluloses, carboxymethylcellulose), other hydrophobic cellulosicmaterials or compounds (e.g., cellulose acetate phthalate,hydroxypropylmethylcellulose phthalate), polyvinyl acetate polymers(e.g., polyvinyl acetate phthalate), polymers or copolymers derived fromacrylic and/or methacrylic acid esters, zein, waxes, shellac,hydrogenated vegetable oils, and mixtures thereof. The hydrophobicpolymer is preferably methyl cellulose, ethyl cellulose or propylcellulose, more preferably ethyl cellulose.

The compositions of the invention may be further admixed with one ormore wetting agents (such as polyethoxylated castor oil, polyethoxylatedhydrogenated castor oil, polyethoxylated fatty acid from castor oil,polyethoxylated fatty acid from hydrogenated castor oil) one or morelubricants (such as magnesium stearate, sodium stearyl fumarate, and thelike), one or more buffering agents, one or more colorants, and/or otherconventional ingredients.

In other embodiments, the invention provides oral sustained releasesolid dosage formulations comprising from about 1 mg to 200 mgoxymorphone hydrochloride, preferably from about 5 mg to about 80 mgoxymorphone hydrochloride; and about 80 mg to about 200 mg of asustained release delivery system, preferably from about 120 mg to about200 mg of a sustained release delivery system, more preferably about 160mg of a sustained release delivery system; where the sustained releasedelivery system comprises about 8.3 to about 41.7% locust bean gum,preferably about 25% locust bean gum; about 8.3 to about 41.7% xanthangum, preferably about 25% xanthan gum; about 20 to about 55% dextrose,preferably about 35% dextrose; about 5 to about 20% calcium sulfatedihydrate, preferably about 10% calcium sulfate dihydrate; and about 2to 10% ethyl cellulose, preferably about 5% ethyl cellulose.

In other embodiments, the invention provides oral sustained releasesolid dosage formulations comprising from about 1 mg to 200 mgoxymorphone hydrochloride, preferably from about 5 mg to about 80 mgoxymorphone hydrochloride; and about 200 mg to about 420 mg of asustained release delivery system, preferably from about 300 mg to about420 mg of a sustained release delivery system, more preferably about 360mg of a sustained release delivery system; where the sustained releasedelivery system comprises about 8.3 to about 41.7% locust bean gum,preferably about 25% locust bean gum; about 8.3 to about 41.7% xanthangum, preferably about 25% xanthan gum; about 20 to about 55% dextrose,preferably about 35% dextrose; about 5 to about 20% calcium sulfatedihydrate, preferably about 10% calcium sulfate dihydrate; and about 2to 10% ethyl cellulose, preferably about 5% ethyl cellulose.

The sustained release formulations of oxymorphone are preferably orallyadministrable solid dosage formulations which may be, for example,tablets, capsules comprising a plurality of granules, sublingualtablets, powders, or granules; preferably tablets. The tablets may be anenteric coating or a hydrophilic coating.

The sustained release delivery system in the compositions of theinvention may be prepared by dry granulation or wet granulation, beforethe oxymorphone or pharmaceutically acceptable salt thereof is added,although the components may be held together by an agglomerationtechnique to produce an acceptable product. In the wet granulationtechnique, the components (e.g., hydrophilic compounds, cross-linkingagents, pharmaceutical diluents, cationic cross-linking compounds,hydrophobic polymers, etc.) are mixed together and then moistened withone or more liquids (e.g., water, propylene glycol, glycerol, alcohol)to produce a moistened mass which is subsequently dried. The dried massis then milled with conventional equipment into granules of thesustained release delivery system. Thereafter, the sustained releasedelivery system is mixed in the desired amounts with the oxymorphone orthe pharmaceutically acceptable salt thereof and, optionally, one ormore wetting agents, one or more lubricants, one or more bufferingagents, one or more coloring agents, or other conventional ingredients,to produce a granulated composition. The sustained release deliverysystem and the oxymorphone may be blended with, for example, a highshear mixer. The oxymorphone is preferably finely and homogeneouslydispersed in the sustained release delivery system. The granulatedcomposition, in an amount sufficient to make a uniform batch of tablets,is subjected to tableting in a conventional production scale tabletingmachine at normal compression pressures, i.e., about 2,000-16,000 psi.The mixture should not be compressed to a point where there issubsequent difficulty with hydration upon exposure to liquids.

The average particle size of the granulated composition is from about 50μm to about 400 μm, preferably from about 185 μm to about 265 μm. Theaverage density of the granulated composition is from about 0.3 g/ml toabout 0.8 g/ml, preferably from about 0.5 g/ml to about 0.7 g/ml. Thetablets formed from the granulations are generally from about 6 to about8 kg hardness. The average flow of the granulations are from about 25 toabout 40 g/sec.

In other embodiments, the invention provides sustained release coatingsover an inner core comprising oxymorphone or a pharmaceuticallyacceptable salt thereof. For example, the inner core comprisingoxymorphone or a pharmaceutically acceptable salt thereof may be coatedwith a sustained release film which, upon exposure to liquids, releasesthe oxymorphone or the pharmaceutically acceptable salt thereof from thecore at a sustained rate.

In one embodiment, the sustained release coating comprises at least onewater insoluble compound. The water insoluble compound is preferably ahydrophobic polymer. The hydrophobic polymer may be the same as ordifferent from the hydrophobic polymer used in the sustained releasedelivery system. Exemplary hydrophobic polymers include alkyl celluloses(e.g., C₁₋₆ alkyl celluloses, carboxymethylcellulose), other hydrophobiccellulosic materials or compounds (e.g., cellulose acetate phthalate,hydroxypropylmethylcellulose phthalate), polyvinyl acetate polymers(e.g., polyvinyl acetate phthalate), polymers or copolymers derived fromacrylic and/or methacrylic acid esters, zein, waxes (alone or inadmixture with fatty alcohols), shellac, hydrogenated vegetable oils,and mixtures thereof. The hydrophobic polymer is preferably, methylcellulose, ethyl cellulose or propyl cellulose, more preferably ethylcellulose. The sustained release formulations of the invention may becoated with a water insoluble compound to a weight gain from about 1 toabout 20% by weight.

The sustained release coating may further comprise at least oneplasticizer such as triethyl citrate, dibutyl phthalate, propyleneglycol, polyethylene glycol, or mixtures thereof.

The sustained release coating may also contain at least one watersoluble compound, such as polyvinylpyrrolidones,hydroxypropylmethylcelluloses, or mixtures thereof. The sustainedrelease coating may comprise at least one water soluble compound in anamount from about 1% to about 6% by weight, preferably in an amount ofabout 3% by weight.

The sustained release coating may be applied to the oxymorphone core byspraying an aqueous dispersion of the water insoluble compound onto theoxymorphone core. The oxymorphone core may be a granulated compositionmade, for example, by dry or wet granulation of mixed powders ofoxymorphone and at least one binding agent; by coating an inert beadwith oxymorphone and at least one binding agent; or by spheronizingmixed powders of oxymorphone and at least one spheronizing agent.Exemplary binding agents include hydroxypropylmethylcelluloses.Exemplary spheronizing agents include microcrystalline celluloses. Theinner core may be a tablet made by compressing the granules or bycompressing a powder comprising oxymorphone or the pharmaceuticallyacceptable salt thereof.

In other embodiments, the compositions comprising oxymorphone or apharmaceutically acceptable salt thereof and a sustained releasedelivery system, as described herein, are coated with a sustainedrelease coating, as described herein. In still other embodiments, thecompositions comprising oxymorphone or a pharmaceutically acceptablesalt thereof and a sustained release delivery system, as describedherein, are coated with a hydrophobic polymer, as described herein. Instill other embodiments, the compositions comprising oxymorphone or apharmaceutically acceptable salt thereof and a sustained releasedelivery system, as described herein, are coated with an entericcoating, such as cellulose acetate phthalate,hydroxypropylmethylcellulose phthalate, polyvinylacetate phthalate,methacrylic acid copolymer, shellac, hydroxypropylmethylcellulosesuccinate, cellulose acetate trimelliate, or mixtures thereof. In stillother embodiments, the compositions comprising oxymorphone or apharmaceutically acceptable salt thereof and a sustained releasedelivery system, as described herein, are coated with a hydrophobicpolymer, as described herein, and further coated with an entericcoating, as described herein. In any of the embodiments describedherein, the compositions comprising oxymorphone or a pharmaceuticallyacceptable salt thereof and a sustained release delivery system, asdescribed herein, may optionally be coated with a hydrophilic coatingwhich may be applied above or beneath the sustained release film, aboveor beneath the hydrophobic coating, and/or above or beneath the entericcoating. Preferred hydrophilic coatings comprisehydroxypropylmethylcellulose.

The invention provides methods for treating pain by administering aneffective amount of the sustained release formulations of oxymorphone toa patient in need thereof. An effective amount is an amount sufficientto eliminate all pain or to alleviate the pain (i.e., reduce the paincompared to the pain present prior to administration of the oxymorphonesustained release formulation). “Sustained release” means that theoxymorphone or pharmaceutically acceptable salt thereof is released fromthe formulation at a controlled rate so that therapeutically beneficialblood levels (but below toxic levels) of the oxymorphone orpharmaceutically acceptable salt thereof are maintained over an extendedperiod of time. The sustained release formulations of oxymorphone areadministered in an amount sufficient to alleviate pain for an extendedperiod of time, preferably about 8 hours to about 24 hours, morepreferably for a period of about 12 hours to about 24 hours. Theoxymorphone sustained release oral solid dosage formulations of theinvention may be administered one to four times a day, preferably onceor twice daily, more preferably once daily. The pain may be minor tomoderate to severe, and is preferably moderate to severe. The pain maybe acute or chronic. The pain may be associated with, for example,cancer, autoimmune diseases, infections, surgical traumas, accidentaltraumas or osteoarthritis. The patient may be an animal, preferably amammal, more preferably a human.

In certain embodiments, upon oral ingestion of the oxymorphone sustainedrelease formulation and contact of the formulation with gastrointestinalfluids, the sustained release formulation swells and gels to form ahydrophilic gel matrix from which the oxymorphone is released. Theswelling of the gel matrix causes a reduction in the bulk density of theformulation and provides the buoyancy necessary to allow the gel matrixto float on the stomach contents to provide a slow delivery of theoxymorphone. The hydrophilic matrix, the size of which is dependent uponthe size of the original formulation, can swell considerably and becomeobstructed near the opening of the pylorus. Since the oxymorphone isdispersed throughout the formulation (and consequently throughout thegel matrix), a constant amount of oxymorphone can be released per unittime in vivo by dispersion or erosion of the outer portions of thehydrophilic gel matrix. The process continues, with the gel matrixremaining bouyant in the stomach, until substantially all of theoxymorphone is released.

In certain embodiments, the chemistry of certain of the components ofthe formulation, such as the hydrophilic compound (e.g., xanthan gum),is such that the components are considered to be self-buffering agentswhich are substantially insensitive to the solubility of the oxymorphoneand the pH changes along the length of the gastrointestinal tract.Moreover, the chemistry of the components is believed to be similar tocertain known muco-adhesive substances, such as polycarbophil.Muco-adhesive properties are desirable for buccal delivery systems.Thus, the sustained release formulation can loosely interact with themucin in the gastrointestinal tract and thereby provide another mode bywhich a constant rate of delivery of the oxymorphone is achieved.

The two phenomenon discussed above (buoyancy and muco-adhesiveproperties) are mechanisms by which the sustained release formulationsof the invention can interact with the mucin and fluids of thegastrointestinal tract and provide a constant rate of delivery of theoxymorphone.

When measured by USP Procedure Drug Release USP 23 (incorporated byreference herein in its entirety), the sustained release formulations ofthe invention exhibit an in vitro dissolution rate of about 15% to about50% by weight oxymorphone after 1 hour, about 45% to about 80% by weightoxymorphone after 4 hours, and at least about 80% by weight oxymorphoneafter 10 hours. The in vitro and in vivo release characteristics of thesustained release formulations of the invention may be modified usingmixtures of one or more different water insoluble and/or water solublecompounds, using different plasticizers, varying the thickness of thesustained release film, including providing release-modifying compoundsin the coating, and/or by providing passageways through the coating.

When administered orally to patients the sustained release formulationsof the invention exhibit the following in vivo characteristics: (a) apeak plasma level of oxymorphone occurs within about 2 to about 6 hoursafter administration; (b) the duration of the oxymorphone analgesiceffect is about 8 to about 24 hours; and (c) the relative oxymorphonebioavailability is about 0.5 to about 1.5 compared to an orallyadministered aqueous solution of oxymorphone.

While the compositions of the invention may be administered as the soleactive pharmaceutical compound in the methods described herein, they canalso be used in combination with one or more compounds which are knownto be therapeutically effective against pain.

The invention also provides pharmaceutical kits comprising one or morecontainers filled with one or more of the compositions of the invention.The kits may further comprise other pharmaceutical compounds known inthe art to be therapeutically effective against pain, and instructionsfor use.

EXAMPLES

The following examples are for purposes of illustration only and are notintended to limit the scope of the appended claims.

Examples 1 and 2

Two sustained release delivery systems were prepared by dry blendingxanthan gum, locust bean gum, calcium sulfate dehydrate, and dextrose ina high speed mixed/granulator for 3 minutes. A slurry was prepared bymixing ethyl cellulose with alcohol. While running choppers/impellers,the slurry was added to the dry blended mixture, and granulated foranother 3 minutes. The granulation was then dried to a LOD (loss ondrying) of less than about 10% by weight. The granulation was thenmilled using 20 mesh screen. The relative quantities of the ingredientsare listed in Table 1. TABLE 1 Sustained Release Delivery System Example1 Example 2 Excipient % % Locust Bean Gum, FCC 25.0 30.0 Xanthan Gum, NF25.0 30.0 Dextrose, USP 35.0 40.0 Calcium Sulfate Dihydrate, NF 10.0 0.0Ethylcellulose, NF  5.0 0.0 Alcohol, SD3A (Anhydrous)¹ (10)¹   (20.0)¹Total 100.0  100.0¹Volatile, removed during processing

Examples 3 to 7

A series of tablets containing different amounts of oxymorphonehydrochloride were prepared using the sustained release delivery systemof Example 1. The quantities of ingredients per tablet are listed inTable 2. TABLE 2 Ex. 3 Ex. 4 Ex. 5 Ex. 6 Ex. 7 Component mg mg mg mg mgOxymorphone HCl, USP 5 10 20 40 80 Sustained release 160 160 160 160 160delivery system Silicified 20 20 20 20 20 microcrystalline cellulose,N.F. Sodium stearyl 2 2 2 2 2 fumarate, NF Total weight 187 192 202 222262 OPADRY ® (colored) 7.48 7.68 8.08 8.88 10.48 OPADRY ® (clear) 0.940.96 1.01 1.11 1.31

Examples 8 and 9

Two batches of tablets were prepared as described above for Examples1-7, using the sustained release delivery system of Example 1. One batchwas formulated to provide relatively fast sustained release, the otherbatch was formulated to provide relatively slow sustained release.Compositions of the tablets are shown in Table 3. TABLE 3 Example 8Example 9 slow release fast release Ingredients mg/tablet mg/tabletOxymorphone HCl, USP 20 20 Sustained Release Delivery 360 160 SystemSilicified Microcrystalline 20 20 Cellulose, NF Sodium stearyl fumarate,NF 4 2 Coating (color) 12.12 12.12 Total weight 416.12 214.12

The tables of Examples 8 and 9 were tested for in vitro release rateaccording to USP Procedure Drug Release USP 23. The results are shown inTable 4. TABLE 4 Example 8 Example 9 Time (hr) slow release fast release0.5 18.8% 21.3% 1 27.8% 32.3% 2 40.5% 47.4% 3 50.2% 58.5% 4 58.1% 66.9%5 64.7% 73.5% 6 70.2% 78.6% 8 79.0% 86.0% 10 85.3% 90.6% 12 89.8% 93.4%

Example 10 Clinical Study

A clinical study was conducted to (1) assess the relativebioavailability (rate and extent of absorption) of oxymorphone sustainedrelease (20 mg) (fast release formulation of Example 9) compared to oralsolution oxymorphone (10 mg) under fasted conditions, (2) to assess therelative bioavailability of oxymorphone sustained release (20 mg)compared to oral solution oxymorphone (10 mg) under fed conditions, (3)to assess the relative bioavailability of oxymorphone sustained release(20 mg) fed compared to oxymorphone sustained release (20 mg) fasted,(4) to assess the relative bioavailability of oral solution oxymorphonefed compared to oral solution oxymorphone fasted, and (5) to assess therelative safety and tolerability of sustained release oxymorphone (20mg) under fed and fasted conditions.

This study had a single-center, open-label, analytically blinded,randomized, four-way crossover design. Subjects randomized to TreatmentA and Treatment C, as described below, were in a fasted state followinga 10-hour overnight fast. Subjects randomized to Treatment B andTreatment D, as described below, were in the fed state, having had ahigh fat meal, completed ten minutes prior to dosing. There was a 14-daywashout interval between the four dose administrations. The subjectswere confined to the clinic during each study period. Subjects assignedto receive Treatment A and Treatment B were discharged from the clinicon Day 3 following the 48-hour procedures, and subjects assigned toreceive Treatment C and Treatment D were discharged from the clinic onDay 2 following the 36-hour procedures. On Day 1 of each study periodthe subjects received one of four treatments:

Treatments A and B were of oxymorphone sustained release 20 mg tablets.Subjects randomized to Treatment A received a single oral dose of one 20mg oxymorphone sustained release tablet taken with 240 ml of water aftera 10-hour fasting period. Subjects randomized to Treatment B received asingle oral dose of one 20 mg oxymorphone sustained release tablet takenwith 240 ml of water 10 minutes after a standardized high fat meal.

Treatments C and D were of oxymorphone HCl solutions, USP, 1.5 mg/mlinjection 10 ml vials. Subjects randomized to Treatment C received asingle oral dose of 10 mg (6.7 ml) oxymorphone solution taken with 240ml of water after a 10-hour fasting period. Subjects randomized toTreatment D received a single oral dose of 10 mg (6.7 ml) oxymorphonesolution taken with 240 ml of water 10 minutes after a standardizedhigh-fat meal.

A total of 28 male subjects were enrolled in the study, and 24 subjectscompleted the study. The mean age of the subjects was 27 years (range of19 through 38 years), the mean height of the subjects was 69.6 inches(range of 64.0 through 75.0 inches), and the mean weight of the subjectswas 169.0 pounds (range 117.0 through 202.0 pounds). The subjects werenot to consume any alcohol-, caffeine-, or xanthine-containing foods orbeverages for 24 hours prior to receiving study medication for eachstudy period. Subjects were to be nicotine and tobacco free for at least6 months prior to enrolling in the study. In addition, over-the-countermedications were prohibited 7 days prior to dosing and during the study.Prescription medications were not allowed 14 days prior to dosing andduring the study.

The subjects were screened within 14 days prior to study enrollment. Thescreening procedure included medical history, physical examination(height, weight, frame size, vital signs, and ECG), and clinicallaboratory tests (hematology, serum chemistry, urinalysis, HIV antibodyscreen, Hepatitis B surface antigen screen, Hepatitis C antibody screen,and a screen for cannabinoids).

During the study, the subjects were to remain in an upright position(sitting or standing) for 4 hours after the study drug was administered.Water was restricted 2 hours predose to 2 hours postdose. During thestudy, the subjects were not allowed to engage in any strenuousactivity.

Subjects reported to the clinic on the evening prior to each dosing. Thesubjects then observed a 10-hour overnight fast. On Day 1, subjectsrandomized to Treatment B and Treatment D received a high-fat breakfastwithin 30 minutes prior to dosing. A standardized meal schedule was theninitiated with lunch 4 hours postdose, dinner 10 hours postdose, and asnack 13 hours postdose. On Day 2, a standardized meal was initiatedwith breakfast at 0815, lunch at 1200, and dinner at 1800. Subjectsrandomized to Treatment A and Treatment B received a snack at 2100 onDay 2.

Vital signs (sitting for 5 minutes and consisting of blood pressure,pulse, respiration, and temperature), and 12-lead ECG were assessed atthe—13 hour point of each check-in period and at the completion of eachperiod. A clinical laboratory evaluation (hematology, serum chemistry,urinalysis) and a brief physical examination were performed at the—13hour of each check-in period and at the completion of the each period.Subjects were instructed to inform the study physician and/or nurses ofany adverse events that occurred during the study.

Blood samples (7 ml) were collected during each study period at the 0hour (predose), and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16,20, 24, 30, 36, and 48 hours post-dose (19 samples) for subjectsrandomized to Treatment A and Treatment B. Blood samples (7 ml) werecollected during each study period at the 0 hour (predose), and at 0.25,0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 20, and36 hours post-dose (21 samples) for subjects randomized to Treatment Cand Treatment D. A total of 80 blood samples (560 ml) per subject weredrawn during the study for drug analysis. Plasma samples were separatedby centrifugation, and then frozen at −70° C., and kept frozen untilassayed.

An LC/MS/MS method was developed and validated for the determination ofoxymorphone in human EDTA plasma. Samples were spiked with internalstandard, d₃ oxymorphone, and placed on the RapidTrace® (ZymarkCorporation, Hopkinton, Mass.) for automatic solid phase extraction.Extracts were dried under nitrogen and reconstituted with acetonitrilebefore injection onto an LC/MS/MS. The Perkin Elmer Sciex API III+, orequivalent, using a turbo ion spray interface was employed in thisstudy. Positive ions were monitored in the MRM mode.

The pharmacokinetic parameters shown in Table 5 were computed from theplasma oxymorphone concentration-time data. TABLE 5 AUC(0-t) Area underthe drug concentration-time curve from time zero to the time of the lastquantifiable concentration (Ct), calculated using linear trapezoidalsummation. AUC(0-inf) Area under the drug concentration-time curve fromtime zero to infinity. AUC(0-inf) = AUC(0-t) + Ct/Kel, where Kel is theterminal elimination rate constant. AUC(0-24) Partial area under thedrug concentration-time curve from time zero to 24 hours. Cmax Maximumobserved drug concentration. Tmax Time of the observed maximum drugconcentration. Kel Elimination rate constant based on the linearregression of the terminal linear portion of the LN(concentration) timecurve. T½el Half life, the time required for the concentration todecline by 50%, calculated as LN(2)/Kel

Terminal elimination rate constants were computed using linearregression of a minimum of three time points, at least two of which wereconsecutive. Kel values for which correlation coefficients were lessthan or equal to 0.8 were not reported in the pharmacokinetic parametertables or included in the statistical analysis. Thus, T1/2el,AUC(0-inf), C1/F, MRT, and LN-transformed T1/2el, AUC(0-inf), and C1/Fwere also not reported in these cases.

A parametric (normal-theory) general linear model was applied to each ofthe above parameters (excluding Tmax and Frel), and the LN-transformedparameters Cmax, AUC(0-24), AUC(0-t), AUC(0-inf), C1/F, and T1/2el.Initially, the analysis of variance (ANOVA) model included the followingfactors: treatment, sequence, subject within sequence, period, andcarryover effect. If carryover effect was not significant, it wasdropped from the model. The sequence effect was tested using the subjectwithin sequence mean square, and all other main effects were testedusing the residual error (error mean square). The following treatmentcomparisons of relative rate and extent of absorption were made:Treatment B versus Treatment A, Treatment A versus Treatment C (dosenormalized to 20 mg). Treatment B versus Treatment D (dose normalized to20 mg), and Treatment D versus Treatment C (dose normalized to 20 mg forboth treatments). The 90% confidence intervals of the ratios of thetreatment least squares parameter means were calculated. Tmax wasanalyzed using the Wilcoxon Signed Ranks test. Summary statistics werepresented for Frel.

Plasma oxymorphone concentrations were listed by subject at eachcollection time and summarized using descriptive statistics.Pharmacokinetic parameters were also listed by subject and summarizedusing descriptive statistics.

A total of 26 analytical runs were required to process the clinicalsamples from this study. Of these 26 analytical runs, 26 were acceptablefor oxymorphone. Standard curves for the 26 analytical runs in EDTAplasma used in this study covered a range of 0.0500 to 20.000 mg/ml witha limit of quantitation of 0.0500 ng/ml for both compounds. Qualitycontrol samples analyzed with each analytical run had coefficients ofvariation less than or equal to 14.23% for oxymorphone.

A total of 28 subjects received at least one treatment. Only subjectswho completed all 4 treatments were included in the summary statisticsand statistical analysis.

The mean oxymorphone plasma concentration versus time curves forTreatments A, B, C, and D are presented in FIG. 1 (linear scale, withoutstandard deviation).

Individual concentration versus time curves were characterized bymultiple peaks which occurred in the initial 12-hour period followingthe dose. In addition, a small “bump” in plasma oxymorphoneconcentration was generally observed in the 24 to 48 hour post-doseperiod.

The arithmetic means of the plasma oxymorphone pharmacokineticparameters and the statistical comparisons for Treatment B versusTreatment A are summarized in Table 6. TABLE 6 Summary of thePharmacokinetic Parameters of Plasma Oxymorphone for Treatments B and APlasma Oxymorphone Treatment A Treatment B Pharmacokinetic ArithmeticArithmetic Mean Parameters Mean SD Mean SD 90% CI Ratio Cmax (ng/ml)1.7895 0.6531 1.1410 0.4537 125.4-191.0 158.2 Tmax (hr) 5.65 9.39 5.577.14 Auc (0-24) (ng * hr/ml) 14.27 4.976 11.64 3.869 110.7-134.0 122.3AUC (O-t) (ng * hr/ml) 19.89 6.408 17.71 8.471 100.2-123.6 111.9 AUC(O-inf) (ng * hr/ml) 21.29 6.559 19.29 5.028 105.3-133.9 119.6 T ½ el(hr) 12.0 3.64 12.3 3.99  57.4-155.2 106.3Treatment B = 1 × 20 mg oxymorphone sustained release Tablet, Fed: testTreatment A = 1 × 20 mg oxymorphone sustained release Tablet, Fasted:reference

The arithmetic means of the plasma oxymorphone pharmacokineticparameters and the statistical comparisons for Treatment A versusTreatment C are summarized in Table 7. TABLE 7 Summary of thePharmacokinetic Parameters of Plasma Oxymorphone for Treatments A and CPlasma Oxymorphone Treatment A Treatment C Pharmacokinetic ArithmeticArithmetic Mean Parameters Mean SD Mean SD 90% CI Ratio Cmax (ng/ml)1.1410 0.4537 2.2635 1.0008 33.4-66.0  49.7 Tmax (hr) 5.57 7.14 0.9781.14 Auc (0-24) (ng * hr/ml) 11.64 3.869 12.39 4.116 82.8-104.6 93.7 AUC(0-I) (ng * hr/ml 17.71 8.471 14.53 4.909 107.7-136.3  122.0 AUC (0-inf)(ng * hr/ml) 19.29 5.028 18.70 6.618 80.2-108.4 94.3 T ½ el (hr) 12.33.99 16.2 11.4 32.9-102.1 67.5Treatment A = 1 × 20 mg oxymorphone sustained release Tablet, Fasted:testTreatment C = 10 mg/6.7 ml oxymorphone HCI Oral Solution, Fasted: DoseNormalized to 20 ng: reference.

The arithmetic means of the plasma oxymorphone pharmacokineticparameters and the statistical comparisons for Treatment D versusTreatment C are summarized in Table 8. TABLE 8 Summary of thePharmacokinetic Parameters of Plasma Oxymorphone for Treatments A and CPlasma Oxymorphone Treatment B Treatment D Pharmacokinetic ArithmeticArithmetic Mean Parameters Mean SD Mean SD 90% CI Ratio Cmax (ng/ml)1.7895 0.6531 3.2733 1.3169 42.7-65.0 50.0 Tmax (hr) 5.65 9.39 1.110.768 Auc (0-24) (ng * hr/ml) 14.27 4.976 17.30 5.259 74.4-90.1 82.2 AUC(0-t) (ng * hr/ml) 19.89 6.408 19.28 6.030  92.5-114.1 103.3 AUC (0-inf)21.29 6.559 25.86 10.03 75.0-95.2 85.1 (ng * hr/ml) T ½ el (hr) 12.03.64 20.6 19.3 31.9-86.1 59.0Treatment B = 1 × 20 mg oxymorphone sustained release Tablet, Fed: testTreatment D = 10 mg/6.7 ml oxymorphone HCI Oral Solution, Fed: DoseNormalized to 20 mg: reference.

The arithmetic means of the plasma oxymorphone pharmacokineticparameters and the statistical comparisons for Treatment D versusTreatment C are summarized in Table 9. TABLE 9 Summary of thePharmacokinetic Parameters of Plasma Oxymorphone for Treatments A and CPlasma Oxymorphone Treatment D Treatment C Pharmacokinetic ArithmeticArithmetic Mean Parameters Mean SD Mean SD 90% CI Ratio Cmax (ng/ml)3.2733 1.3169 2.2635 1.0008 129.7-162.3 146.0 Tmax (hr) 1.11 0.768 0.9781.14 Auc (0-24) (ng * hr/ml) 17.30 5.259 12.39 4.116 128.5-150.3 139.4AUC (0-t) (ng * hr/ml) 19.20 6.030 14.53 4.909 117.9-146.5 132.2 AUC(0-inf) 25.86 10.03 18.70 6.618 118.6-146.6 132.6 (ng * hr/ml) T ½ el(hr) 20.6 19.3 16.2 11.4  87.3-155.9 121.6Treatment D = 10 mg/6.7 ml oxymorphone HCI Oral Solution, Fed: DoseNormalized to 20 mg: test.Treatment C = 10 mg/6.7 ml oxymorphone HCI Oral Solution, Fasted: DoseNormalized to 20 mg: reference.

The relative bioavailability calculations are summarized in Table 10.TABLE 10 Mean (S.D.) Relative Oxymorphone Bioavailability Determinedfrom AUC (0-inf) and AUC (0-24) Frel BA Frel AC Frel BD Frel DC AUC(0-inf) 1.169 (0.2041) 1.040 (0.1874) 0.8863 (0.2569) 1.368 (0.4328) AUC(0-24) 1.299 (0.4638) (0.9598) (0.2151) 0.8344  (0.100) 1.470 (0.3922)

The objectives of this study were to assess the relative bioavailabilityof oxymorphone from oxymorphone sustained release (20 mg) compared tooxymorphone oral solution (10 mg) under both fasted and fed conditions,and to determine the effect of food on the bioavailability ofoxymorphone from the sustained release formulation and from the oralsolution.

The presence of a high fat meal had a substantial effect on theoxymorphone Cmax, but less of an effect on oxymorphone AUC fromoxymorphone sustained release tablets. Least Squares (LS) mean Cmax was58% higher and LS mean AUC(0-t) and AUC(0-inf) were 18% higher for thefed condition (Treatment B) compared to the fasted condition (TreatmentA) based on LN-transformed data. This was consistent with the relativebioavailability determination from AUC(0-inf) since mean Frel was 1.17.Individual Frel values based on AUC (0-24) were similar (less than 20%different) to Frel values based on AUC(0-inf) for all but 2 subjects.Comparison of mean Frel from AUC(0-inf) to mean Frel from AUC (0-24) ismisleading, because not all subjects had a value for AUC(0-inf). MeanTmax values were similar (approximately 5.6 hours), and no significantdifferent in Tmax was shown using nonparametric analysis. Half valuedurations were significantly different between the two treatments.

The effect of food on oxymorphone bioavailability from the oral solutionwas more pronounced, particularly in terms of AUC. LS mean Cmax was 50%higher and LS mean AUC(0-t) and AUC(0-inf) were 32-34% higher for thefed condition (Treatment D) compared to the fasted condition (TreatmentC) based on LN-transformed data. This was consistent with the relativebioavailability determination from AUC(0-inf) since mean Frel was 1.37.Individual Frel values based on AUC(0-24) were similar (less than 20%different) to Frel values based on AUC(0-inf.) for all but 5 subjects.Comparison of mean Frel from AUC(0-inf) to mean Frel from AUC(0-24) ismisleading because not all subjects had a value for AUC(0-inf). MeanTmax (approximately 1 hour) was similar for the two treatments and nosignificant difference was shown.

Under fasted conditions, oxymorphone sustained release 20 mg tabletsexhibited similar extent of oxymorphone availability compared to 10 mgoxymorphone oral solution normalized to a 20 mg dose (Treatment A versusTreatment C). From LN-transformed data, LS mean AUC(0-t) was 17% higherfor oxymorphone sustained release, whereas LS mean AUC(0-inf) valueswere nearly equal (mean ratio=99%). However, AUC(0-t) is not the bestparameter to evaluate bioavailability since the plasma concentrationswere measured for 48 hours for the sustained release formulation versus36 hours for the oral solution. Mean Frel values calculated fromAUC(0-inf) and AUC(0-24), (1.0 and 0.96, respectively) also showedsimilar extent of oxymorphone availability between the two treatments.

There were differences in parameters reflecting rate of absorption. LSmean Cmax was 49% lower for oxymorphone sustained release tabletscompared to the dose-normalized oral solution, based on LN-transformeddata. Half-value duration was significantly longer for the sustainedrelease formulation (means, 12 hours versus 2.5 hours).

Under fed conditions, oxymorphone availability from oxymorphonesustained release 20 mg was similar compared to 10 mg oxymorphone oralsolution normalized to a 20 mg dose (Treatment B versus Treatment D).From LN-transformed data, LS mean AUC(0-inf) was 12% lower foroxymorphone sustained release. Mean Frel values calculated fromAUC(0-inf) and AUC(0-24), (0.89 and 0.83 respectively) also showedsimilar extent of oxymorphone availability from the tablet. There weredifferences in parameters reflecting rate of absorption. LS mean Cmaxwas 46% lower for oxymorphone sustained release tablets compared to thedose-normalized oral solution, based on LN-transformed data. Mean Tmaxwas 5.7 hours for the tablet compared to 1.1 hours for the oralsolution. Half-value duration was significantly longer for the sustainedrelease formulation (means, 7.8 hours versus 3.1 hours).

The presence of a high fat meal did not appear to substantially affectthe availability following administration of oxymorphone sustainedrelease tablets. LS mean ratios were 97% for AUC(0-t) and 91% for Cmax(Treatment B versus A), based on LN-transformed data. This wasconsistent with the relative bioavailability determination fromAUC(0-24), since mean Frel was 0.97. AUC(0-inf) was not a reliablemeasure for bioavailability since half-life could not be estimatedaccurately, and in many cases at all. Half-life estimates were notaccurate because in the majority of subjects, the values for half-lifewere nearly as long or longer (up to 2.8 times longer) as the samplingperiod. Mean Tmax was later for the fed treatment compared to the fastedtreatment (5.2 and 3.6 hours, respectively), and difference wassignificant.

Under fasted conditions, oxymorphone sustained release 20 mg tabletsexhibited similar availability compared to 10 mg oxymorphone oralsolution normalized to a 20 mg dose (Treatment A versus Treatment C).From LN-transformed data, LS mean ratio for AUC(0-t) was 104.5%. MeanFrel (0.83) calculated from AUC(0-24) also showed similar extent ofoxymorphone availability between the two treatments. There weredifferences in parameters reflecting rate of absorption. LS mean Cmaxwas 57% lower for oxymorphone sustained release tablets compared to thedose-normalized oral solution. Mean Tmax was 3.6 hours for the tabletcompared to 0.88 for the oral solution. Half-value duration wassignificantly longer for the sustained release formulation (means, 11hours versus 2.2 hours).

Under fed conditions, availability from oxymorphone sustained release 20mg was similar compared to 10 mg oxymorphone oral solution normalized toa 20 mg dose (Treatment B versus Treatment D). From LN-transformed data,LS mean AUC(0-t) was 14% higher for oxymorphone sustained release. MeanFrel (0.87) calculated from AUC (0-24) also indicated similar extent ofavailability between the treatments. There were differences inparameters reflecting rate of absorption. LS mean Cmax was 40% lower foroxymorphone sustained release tablets compared to the dose-normalizedoral solution. Mean Tmax was 5.2 hours for the tablet compared to 1.3hour for the oral solution. Half-value duration was significantly longerfor the sustained release formulation (means, 14 hours versus 3.9hours).

The extent of oxymorphone availability from oxymorphone sustainedrelease 20 mg tablets was similar under fed and fasted conditions sincethere was less than a 20% difference in LS mean AUC(0-t) and AUC(0-inf)values for each treatment, based on LN-transformed data. Tmax wasunaffected by food; however, LS mean Cmax was increased 58% in thepresence of the high fat meal. Both rate and extent of oxymorphoneabsorption from the oxymorphone oral solution were affected by foodsince LS mean Cmax and AUC values were increased approximately 50 and30%, respectively. Tmax was unaffected by food. Under both fed andfasted conditions, oxymorphone sustained release tablets exhibitedsimilar extent of oxymorphone availability compared to oxymorphone oralsolution since there was less than a 20% difference in LS mean AUC(0-t)and AUC(0-inf) values for each treatment.

Bioavailability following oxymorphone sustained release 20 mg tabletswas also similar under fed and fasted conditions since there was lessthan a 20% difference in LS mean Cmax and AUC values for each treatment.Tmax was later for the fed condition. The presence of food did notaffect the extent of availability from oxymorphone oral solution sinceLS mean AUC values were less than 20% different. However, Cmax wasdecreased 35% in the presence of food. Tmax was unaffected by food.Under both fed and fasted conditions, oxymorphone sustained releasetablets exhibited similar extent of availability compared to oxymorphoneoral solution since there was less than a 20% difference in LS mean AUCvalues for each treatment.

Various modifications of the invention, in addition to those describedherein, will be apparent to one skilled in the art from the foregoingdescription. Such modifications are intended to fall within the scope ofthe appended claims.

1. An oral sustained release formulation comprising oxymorphone or apharmaceutically acceptable salt thereof and a sustained releasedelivery system, wherein the sustained release delivery system comprisesat least one hydrophilic compound, at least one cross-linking agent andat least one pharmaceutical diluent.
 2. The sustained releaseformulation of claim 1, wherein the ratio of oxymorphone or apharmaceutically acceptable salt thereof to the sustained releasedelivery system is from about 1:0.5 to about 1:25.
 3. The sustainedrelease formulation of claim 1, wherein the oxymorphone orpharmaceutically acceptable salt thereof is present in an amount ofabout 1 mg to about 200 mg in the formulation.
 4. The sustained releaseformulation of claim 3, wherein the oxymorphone or pharmaceuticallyacceptable salt thereof is present in an amount of about 5 mg to about80 mg in the formulation.
 5. The sustained release formulation of claim1, wherein the sustained release delivery system is present in an amountof about 80 mg to about 420 mg in the formulation.
 6. The sustainedrelease formulation of claim 5, wherein the sustained release deliverysystem is present in an amount of about 80 mg to about 360 mg in theformulation.
 7. The sustained release formulation of claim 6, whereinthe sustained release delivery system is present in an amount of about80 mg to about 200 mg in the formulation.
 8. The sustained releaseformulation of claim 1, wherein the at least one hydrophilic compound ispresent in the sustained release delivery system in an amount of about20% to about 80% by weight; the at least one cross-linking agent ispresent in the sustained release delivery system in an amount of about0.5% to about 80% by weight; and the at least one pharmaceutical diluentis present in the sustained release delivery system in an amount ofabout 20% to about 80% by weight.
 9. The sustained release formulationof claim 8, wherein the at least one hydrophilic compound is present inthe sustained release delivery system in an amount of about 20% to about60% by weight; the at least one cross-linking agent is present in thesustained release delivery system in an amount of about 2% to about 54%by weight; and the at least one pharmaceutical diluent is present in thesustained release delivery system in an amount of about 20% to about 80%by weight.
 10. The sustained release formulation of claim 9, wherein theat least one hydrophilic compound is present in the sustained releasedelivery system in an amount of about 40% to about 60% by weight; the atleast one cross-linking agent is present in the sustained releasedelivery system in an amount of about 20% to about 30% by weight; andthe at least one pharmaceutical diluent is present in the sustainedrelease delivery system in an amount of about 40% to about 80% byweight.
 11. The sustained release formulation of claim 1, wherein the atleast one hydrophilic compound is a heteropolysaccharide gum.
 12. Thesustained release formulation of claim 1, wherein the at least onehydrophilic compound is at least one compound selected from xanthan gum,tragacanth gum, a pectin, acacia, karaya, agar, carrageenan, and agellan gum.
 13. The sustained release formulation of claim 1, whereinthe at least one hydrophilic compound is a xanthan gum or a derivativethereof.
 14. The sustained release formulation of claim 1, wherein theat least one cross-linking agent is a homopolysaccharide gum.
 15. Thesustained release formulation of claim 14, wherein thehomopolysaccharide gum is a locust bean gum or a guar gum.
 16. Thesustained release formulation of claim 1, wherein the at least onepharmaceutical diluent is at least one compound selected from starch,lactose, dextrose, sucrose, microcrystalline cellulose, sorbitol,xylitol, and fructose.
 17. The sustained release formulation of claim 1,wherein the ratio of the at least one hydrophilic compound to the atleast one cross-linking agent is from about 1:9 to about 9:1.
 18. Thesustained release formulation of claim 1, wherein the ratio of the atleast one pharmaceutical diluent to the at least one hydrophiliccompound is from about 1:8 to about 8:1.
 19. A method for treating apatient suffering from pain comprising administering an effective amountof the sustained release formulation of claim
 1. 20. The sustainedrelease formulation of claim 1, wherein the sustained release deliverysystem further comprises at least one hydrophobic polymer.
 21. Thesustained release formulation of claim 20, wherein the at least onehydrophobic polymer is present in the sustained release delivery systemin an amount of about 0.5% to about 20% by weight.
 22. The sustainedrelease formulation of claim 21, wherein the at least one hydrophobicpolymer is present in the sustained release delivery system in an amountof about 2% to about 10% by weight.
 23. The sustained releaseformulation of claim 20, wherein the hydrophobic polymer is at least onecompound selected from an alkylcellulose, a hydrophobic cellulosicmaterial, a polyvinyl acetate polymer, a polymer or copolymer of acrylicand methacrylic acid esters, zein, a wax, a shellac and a hydrogenatedvegetable oil.
 24. The sustained release formulation of claim 20,wherein the alkyl cellulose is ethyl cellulose.
 25. A method fortreating a patient suffering from pain comprising administering aneffective amount of the sustained release formulation of claim
 20. 26.The sustained release formulation of claim 1, wherein the sustainedrelease delivery system further comprises at least one cationiccross-linking compound.
 27. The sustained release formulation of claim26, wherein the at least one cross-linking compound is present in thesustained release delivery system in an amount of about 0.5% to about30% by weight.
 28. The sustained release formulation of claim 27,wherein the at least one cross-linking compound is present in thesustained release delivery system in an amount of about 5% to about 20%by weight.
 29. The sustained release formulation of claim 26, whereinthe at least one cationic cross-linking compound is at least onecompound selected from a monovalent metal cation, a multivalent metal,cation, and an inorganic salt.
 30. The sustained release formulation ofclaim 29, wherein the inorganic salt is an alkali metal sulfate, analkali metal chloride, an alkali metal borate, an alkali metal bromide,an alkali metal citrate, an alkali metal acetate, an alkali metallactate, an alkaline earth metal sulfate, an alkaline earth metalchloride, an alkaline earth metal borate, an alkaline earth metalbromide, an alkaline earth metal citrate, an alkaline earth metalacetate, an alkaline earth metal lactate, and a mixture thereof.
 31. Thesustained release formulation of claim 26, wherein the at least onecationic cross-linking compound is at least one compound selected fromcalcium sulfate, sodium chloride, potassium sulfate, sodium carbonate,lithium chloride, tripotassium phosphate, sodium borate, potassiumbromide, potassium fluoride, sodium bicarbonate, calcium chloride,magnesium chloride, sodium citrate, sodium acetate, calcium lactate,magnesium sulfate, and sodium fluoride.
 32. A method for treating apatient suffering from pain comprising administering an effective amountof the sustained release formulation of claim
 26. 33. The sustainedrelease formulation of claim 1, wherein the sustained releaseformulation has an in vitro dissolution rate of about 15% to about 50%by weight oxymorphone after about 1 hour.
 34. The sustained releaseformulation of claim 1, wherein the sustained release formulation has asin vitro dissolution rate of about 45% to about 80% by weightoxymorphone after about 4 hours.
 35. The sustained release formulationof claim 1, wherein the sustained release formulation has as in vitrodissolution rate of at least about 80% by weight oxymorphone after about10 hours.
 36. The sustained release formulation of claim 1, furthercomprising an outer coating, wherein the outer coating comprises atleast one hydrophobic polymer.
 37. The sustained release formulation ofclaim 36, wherein the hydrophobic polymer is at least one compoundselected from an alkyl cellulose, a hydrophobic cellulosic material, apolyvinyl acetate polymer, a polymer or copolymer of acrylic andmethacrylic acid esters, zein, a wax, a shellac and a hydrogenatedvegetable oil.
 38. The sustained release formulation of claim 36,wherein the hydrophobic polymer is present on the sustained releaseformulation to a weight gain from about 1% to about 20% by weight. 39.The sustained release formulation of claim 1, further comprising anouter coating, wherein the outer coating comprises at least oneplasticizer.
 40. A sustained release formulation comprising oxymorphoneor a pharmaceutically acceptable salt thereof and a sustained releasedelivery system; wherein the sustained release delivery system comprisesat least one hydrophilic compound, at least one cationic cross-linkingcompound, and at least one pharmaceutical diluent.
 41. The sustainedrelease formulation of claim 40, wherein the ratio of oxymorphone or apharmaceutically acceptable salt thereof to the sustained releasedelivery system is from about 1:0.5 to about 1:25.
 42. The sustainedrelease formulation of claim 40, wherein the oxymorphone orpharmaceutically acceptable salt thereof is present in an amount ofabout 1 mg to about 200 mg in the formulation.
 43. The sustained releaseformulation of claim 42, wherein the oxymorphone or pharmaceuticallyacceptable salt thereof is present in an amount of about 5 mg to about80 mg in the formulation.
 44. The sustained release formulation of claim40, wherein the sustained release delivery system is present in anamount of about 80 mg to about 420 mg in the formulation.
 45. Thesustained release formulation of claim 44, wherein the sustained releasedelivery system is present in an amount of about 80 mg to about 360 mgin the formulation.
 46. The sustained release formulation of claim 45,wherein the sustained release delivery system is present in an amount ofabout 80 mg to about 200 mg in the formulation.
 47. The sustainedrelease formulation of claim 40, wherein the at least one hydrophiliccompound is present in the sustained release delivery system in anamount of about 20% to about 80% by weight; the at least one cationiccross-linking agent is present in the sustained release delivery systemin an amount of about 0.5% to about 30% by weight; and the at least onepharmaceutical diluent is present in the sustained release deliverysystem in an amount of about 20% to about 80% by weight.
 48. Thesustained release formulation of claim 40, wherein the at least onehydrophilic compound is present in the sustained release delivery systemin an amount of about 20% to about 60% by weight; the at least onecationic cross-linking agent is present in the sustained releasedelivery system in an amount of about 5% to about 20% by weight; and theat least one pharmaceutical diluent is present in the sustained releasedelivery system in an amount of about 20% to about 80% by weight. 49.The sustained release formulation of claim 48, wherein the at least onehydrophilic compound is present in the sustained release delivery systemin an amount of about 40% to about 60% by weight; the at least onecationic cross-linking agent is present in the sustained releasedelivery system in an amount of about 5% to about 20% by weight; and theat least one pharmaceutical diluent is present in the sustained releasedelivery system in an amount of about 40% to about 80% by weight. 50.The sustained release formulation of claim 40, wherein the at least onehydrophilic compound is a heteropolysaccharide gum.
 51. The sustainedrelease formulation of claim 40, wherein the at least one hydrophiliccompound is at least one compound selected from xanthan gum, tragacanthgum, a pectin, acacia, karaya, agar, carrageenan, and a gellan gum. 52.The sustained release formulation of claim 40, wherein the at least onehydrophilic compound is a xanthan gum or a derivative thereof.
 53. Thesustained release formulation of claim 40, wherein the at least onecationic cross-linking compound is at least one compound selected from amonovalent metal cation, a multivalent metal cation, and an inorganicsalt.
 54. The sustained release formulation of claim 53, wherein theinorganic salt is an alkali metal sulfate, an alkali metal chloride, analkali metal borate, an alkali metal bromide, an alkali metal citrate,an alkali metal acetate, an alkali metal lactate, an alkaline earthmetal sulfate, an alkaline earth metal chloride, an alkaline earth metalborate, an alkaline earth metal bromide, an alkaline earth metalcitrate, an alkaline earth metal acetate, an alkaline earth metallactate, and a mixture thereof.
 55. The sustained release formulation ofclaim 40, wherein the at least one cationic cross-linking compound is atleast one compound selected from calcium sulfate, sodium chloride,potassium sulfate, sodium carbonate, lithium chloride, tripotassiumphosphate, sodium borate, potassium bromide, potassium fluoride, sodiumbicarbonate, calcium chloride, magnesium chloride, sodium citrate,sodium acetate, calcium lactate, magnesium sulfate, sodium fluoride, andmixtures thereof.
 56. The sustained release formulation of claim 40,wherein the at least one pharmaceutical diluent is at least one compoundselected from starch, lactose, dextrose, sucrose, microcrystallinecellulose, sorbitol, xylitol, and fructose.
 57. A method for treating apatient suffering from pain comprising administering an effective amountof the sustained release formulation of claim
 40. 58. The sustainedrelease formulation of claim 40, wherein the sustained release deliverysystem further comprises at least one hydrophobic polymer.
 59. Thesustained release formulation of claim 58, wherein the at least onehydrophobic polymer is present in the sustained release delivery systemin an amount of about 0.5% to about 20% by weight.
 60. The sustainedrelease formulation of claim 59, wherein the at least one hydrophobicpolymer is present in the sustained release delivery system in an amountof about 2% to about 10% by weight.
 61. The sustained releaseformulation of claim 58, wherein the hydrophobic polymer is at least onecompound selected from an alkyl cellulose, a polyvinyl acetate polymer,a polymer or copolymer derived from acrylic and methacrylic acid esters,zein, a wax, shellac and a hydrogenated vegetable oil.
 62. The sustainedrelease formulation of claim 61, wherein the alkyl cellulose is ethylcellulose.
 63. A method for treating a patient suffering from paincomprising administering an effective amount of the sustained releaseformulation of claim
 58. 64. The sustained release formulation of claim40, wherein the sustained release formulation has an in vitrodissolution rate of about 15% to about 50% by weight oxymorphone afterabout 1 hour.
 65. The sustained release formulation of claim 40, whereinthe sustained release formulation has as in vitro dissolution rate ofabout 45% to about 80% by weight oxymorphone after about 4 hours. 66.The sustained release formulation of claim 40, wherein the sustainedrelease formulation has as in vitro dissolution rate of at least about80% by weight oxymorphone after about 10 hours.
 67. The sustainedrelease formulation of claim 40, further comprising an outer coating,wherein the outer coating comprises at least one hydrophobic polymer.68. The sustained release formulation of claim 67, wherein thehydrophobic polymer is at least one compound selected from an alkylcellulose, a hydrophobic cellulosic material, a polyvinyl acetatepolymer, a polymer or copolymer of acrylic and methacrylic acid esters,zein, a wax, a shellac and a hydrogenated vegetable oil.
 69. Thesustained release formulation of claim 67, wherein the hydrophobicpolymer is present on the sustained release formulation to a weight gainfrom about 1% to about 20% by weight.
 70. The sustained releaseformulation of claim 40, further comprising an outer coating, whereinthe outer coating comprises at least one plasticizer.
 71. A sustainedrelease formulation comprising an inner core and an outer coating,wherein the inner core comprises oxymorphone or a pharmaceuticallyacceptable salt thereof and the outer coating comprises at least onehydrophobic polymer.
 72. The sustained release formulation of claim 71,wherein the hydrophobic polymer is at least one compound selected froman alkyl cellulose, a hydrophobic cellulosic material, a polyvinylacetate polymer, a polymer or copolymer of acrylic and methacrylic acidesters, zein, a wax, a shellac and a hydrogenated vegetable oil.
 73. Thesustained release formulation of claim 71, wherein the hydrophobicpolymer is present on the sustained release formulation to a weight gainfrom about 1% to about 20% by weight.
 74. The sustained releaseformulation of claim 71, wherein the outer coating further comprises atleast one plasticizer.
 75. The sustained release formulation of claim71, wherein the outer coating further comprises at least one watersoluble compound.
 76. A method for treating a patient suffering frompain comprising administering an effective amount of the sustainedrelease formulation of claim
 71. 77-88. (canceled)
 89. The sustainedrelease formulation of claim 1, wherein the at least one hydrophiliccompound is a cellulose ether.
 90. The sustained release formulation ofclaim 89, wherein the cellulose ether is hydroxyalkyl cellulose.
 91. Thesustained release formulation of claim 90, wherein the hydroxyalkylcellulose is selected from hydroxyethyl cellulose, hydroxypropylcellulose, hydroxypropylmethyl-cellulose, and a mixture thereof.
 92. Thesustained release formulation of claim 90, wherein the hydroxyalkylcellulose is hydroxypropylmethyl-cellulose.
 93. The sustained releaseformulation of claim 40, wherein the at least one hydrophilic compoundis a cellulose ether.
 94. The sustained release formulation of claim 93,wherein the cellulose ether is hydroxyalkyl cellulose.
 95. The sustainedrelease formulation of claim 94, wherein the hydroxyalkyl cellulose isselected from hydroxyethyl cellulose, hydroxypropyl cellulose,hydroxypropylmethyl-cellulose, and a mixture thereof.
 96. The sustainedrelease formulation of claim 95, wherein the hydroxyalkyl cellulose ishydroxypropylmethyl-cellulose.
 97. A solid dosage formulation comprisingthe oral sustained release formulation of claim
 1. 98. The solid dosageformulation of claim 97, wherein the solid dosage formulation is atablet.
 99. A solid dosage formulation comprising an oral sustainedrelease formulation from about 5 to about 80 mg oxymorphonehydrochloride and about 80 mg to about 360 mg of a sustained releasedelivery system; wherein the sustained release delivery system comprisesabout 8.3% to about 41.7% by weight locust bean gum, about 8.3% to about41.7% by weight xanthan gum, about 20% to about 55% by weight dextrose,about 5% to about 20% by weight calcium sulfate dihydrate, and about 2%to about 10% ethyl cellulose.
 100. The solid dosage formulation of claim99, wherein the solid dosage formulation is a tablet.